1. Field of the Invention
The present invention is generally directed to methods and compositions for increasing phospholipid catabolism and/or the treatment of lung disease.
2. Background of the Related Art
Lung surfactant is the surface-active agent comprised of phospholipids and proteins that lines pulmonary alveolae. Surfactant stabilizes the alveolar volume by reducing surface tension. This complex consists of approximately 90% phospholipids and 5-10% protein (King, J. Appl. Physiol. Exercise Physiol. 53, 1-8 1982). The protein fraction of the surfactant is composed of nonserum and serum proteins. The major surfactant associated protein is reportedly a 35,000 dalton nonserum, sialoglycoprotein (Bhattacharyya et al., J. Clin. Invest. 55, 914-920, 1975; Shelly et al., Am. J. Obstet. Gynecol. 144, 224-228, 1982; Sueishin and Benson, Biochem. Biophys. Acta 665, 442-453, 1981). The phospholipid component of pulmonary surfactant is largely in the form of dipalmitoylphosphatidylcholine.
Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease that is characterized by the alveolar and interstitial accumulation of a periodic acid-Schiff stain-positive phospholipoprotein derived from the pulmonary surfactant. This disorder is known to occur in primary and secondary forms. Primary PAP is idiopathic. However, PAP also may manifest as a secondary disorder that is associated with hematologic malignancies, such as chronic myeloid leukemia and lymphomas. In addition PAP has been documented in association with occupational exposure to mineral dusts and fumes. Mineral dust exposures associated with PAP include aluminum dust, titanium dioxide, cement dust, fibrous insulation material, and nitrogen dioxide, as reported in several studies. PAP also is thought to result in association with infections, including infection by Nocardia, Mycobacterium tuberculosis, nontuberculous mycobacteria, cytomegalovirus, and fungal infections, such as histoplasmosis and cryptococcosis. PAP also has been described by Ruben and Talamo in patients with AIDS, including AIDS patients with coincident Pneumocystis pneumonia infection. Others have suggested that PAP may be a congenital in origin, resulting from a lysinuric protein intolerance (according to Parto et al) or deficiency of surfactant protein B.
Congenital alveolar proteinosis (CAP) is a specific and severe form of alveolar proteinosis in which the predominant symptoms, which occur shortly after birth, include neonatal respiratory distress, dyspnea, tachypnea, diminished exercise tolerance, feeding difficulty, failure to thrive, and loss of weight. In neonatal respiratory distress, the patient with CAP presents with progressive respiratory failure and marked hypoxemia shortly after birth. In the absence of therapeutic intervention CAP has a 100% mortality rate. To date, the only effective therapeutic intervention has been whole lung transplantation in these patients. However, even with this drastic intervention, remission has been observed.
Thus, the etiology of PAP is varied and the underlying causes of the disorder remain poorly understood. However, in all cases there is an abnormal accumulation of phospholipids in lung tissue. The symptoms of PAP are generally those associated with a syndrome known as phospholipidosis, a generalized condition observed in both animals and humans that is characterized by the appearance of concentric lamellar bodies within cells and the intracellular accumulation of phospholipids. Phospholipidosis is an acquired condition observed in patients treated with a variety of commonly prescribed cationic amphiphilic drugs (CADs) that include amiodarone, gentamicin, fluoxetine, and chloroquine. Phospholipidosis is thought to arise by the inhibition of one or more acidic lysosomal phospholipases. However, the failure to identify the lysosomal phospholipase that is the target for drug-induced phospholipidosis has hindered the understanding of the pathogenesis and significance of this condition.
Treatment of PAP involves periodic therapeutic bronchioalveolar lavages. In such therapy, a periodic whole-lung lavage is administered in which the excessive phospholipids are washed from the lung. This therapy requires hospitalization and specially trained physicians. In severe cases, lung transplantation is required. The current therapies are often inadequate because spontaneous remission, as well as, progressive respiratory failure is often observed. In addition, these therapeutic interventions have attendant complications related to secondary infections. The requirement for such intervention in CAD-induced phospholipidosis greatly diminishes the therapeutic utility of CADs.
Therefore, there remains a need for a better understanding of the causes of phospholipid catabolism disorders and for the identification of new therapeutic interventions for such disorders.